64068-00-4Relevant articles and documents
3,6-DIAMINO-PYRIDAZIN-3-YL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USES AS PRO-APOPTOTIC AGENTS
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Page/Page column 145, (2021/02/05)
Compounds of formula (I) wherein Het1, Het2, R1, R2 and R3 are as defined in the description. Medicaments.
Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
Ratni, Hasane,Ebeling, Martin,Baird, John,Bendels, Stefanie,Bylund, Johan,Chen, Karen S.,Denk, Nora,Feng, Zhihua,Green, Luke,Guerard, Melanie,Jablonski, Philippe,Jacobsen, Bjoern,Khwaja, Omar,Kletzl, Heidemarie,Ko, Chien-Ping,Kustermann, Stefan,Marquet, Anne,Metzger, Friedrich,Mueller, Barbara,Naryshkin, Nikolai A.,Paushkin, Sergey V.,Pinard, Emmanuel,Poirier, Agnès,Reutlinger, Michael,Weetall, Marla,Zeller, Andreas,Zhao, Xin,Mueller, Lutz
, p. 6501 - 6517 (2018/08/17)
SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.
SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
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Paragraph 0362; 0363, (2017/04/04)
Provided herein are novel substituted bicyclic aza-heterocycle sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.